Over the past few years, several research groups in, chiefly, England or the United States of America, have synthesized histamine H.sub.2 -receptor antagonists useful in treating peptic ulcers. Broadly speaking, these compounds can be classed as substituted amidines; e.g., acetamidine, ##STR1## Related compounds include guanidines, ##STR2## mercaptoamidines or isothioureas, ##STR3## tautomeric with the thioureas ##STR4## and ethenediamines, ##STR5## tautomeric with ##STR6## In these new H.sub.2 -receptor antagonists, the amidine usually occurs at one end of a bridging group; i.e., --CH.sub.2 --Y--(CH.sub.2).sub.2 --where Y is S, O, NH or CH.sub.2. The other end of the bridging group has usually been an aromatic heterocycle, most frequently imidazole. The heterocyclic ring can be substituted.
The first drug recognized as a powerful H.sub.2 -receptor antagonist was a thiourea, burimamide--N-methyl-N'-(4-[4(5)-imidazolyl)]butyl)thiourea--having the following formula: ##STR7## The pharmacological properties of this compound are disclosed in The Pharmacological Basis of Therapeutics, Goodman & Gilman 5th Ed. (MacMillan Publishing Co., Inc., New York) page 612. Burimamide was developed by a group of research workers headed by Black and Durant.
A second generation of histamine H.sub.2 -receptor atagonists comprised compounds developed by Black, Durant and co-workers with a structure more or less similar to that of burimamide, but in which there was a permissible interrupting group--oxygen, sulfur or NH--in the alkyl side chain attached to the hetero ring. The most prominent of this group of compounds has been cimetidine, chemically N-cyano-N'-methyl-N"-[2-([(5-methyl-1H-imidazol-4-yl)methyl]thio)ethyl]gua nidine, represented by the formula below: ##STR8##
A large number of patents based upon several original filings Ser. Nos. 230,451; 284,992; 385,027; 481,716; 816,420; 436,285; 542,971; 468,617; 384,993; and 385,027) have issued to Durant et al including, but not limited to, the following U.S. Pat. Nos. 3,950,333; 4,049,672; 4,022,797; 4,137,237; 4,024,271; 4,070,475; 4,154,844; 3,905,984; 4,027,026; 3,932,427; 4,018,928; 3,950,353; 4,053,473; 4,018,931; 4,069,327; 4,151,288; 4,000,296; 4,083,988; 4,129,657; 4,098,898; 4,166,856; 4,072,748; 3,971,786; 4,060,620; 3,876,647; 3,920,822; 3,897,444; 3,975,530; 4,226,874; 4,228,291; 4,230,865 and 4,221,802.
Other disclosed hereto ring systems in addition to imidazole include pyrazole, pyridine, pyrimidine, pyridazine, thiazole, isothiazole, oxazole, isoxazole, triazole, thiadiazole, benzimidazole and tetrahydroimidazo[1,5-a]pyridine, but the greatest emphasis has continued to be placed on compounds having an imidazole ring system. Groupings which may be present at the terminal end of the alkyl or alkylthioalkyl bridging group include, among others, guanidine, cyanoguanidine, urea, nitroethenediamine and thiourea.
Patents referring to thiazole or oxazole ring systems are of particular relevance to this invention. The two basic disclosures by the Durant group are contained in U.S. Pat. Nos. 3,950,333 and 3,950,353, both of which are continuations-in-part of Ser. No. 290,584 which was in turn a continuation-in-part of Ser. No. 230,451. In U.S. Pat. No. 3,950,333, the disclosure relating to thiazoles begins at Example 115, column 37. Thiazoles substituted with a chloro or an alkyl group are described. The thiazole nucleus is then attached at the 2- or 4- position of the thiazole ring to an alkylthioalkyl side chain terminating in an N-cyano-N'-methylguanidine. This disclosure is followed by similar disclosures for isothiazoles, oxazoles and isoxazoles. The disclosure in U.S. Pat. No. 3,950,353 relating to thiazoles begins at Example 110, column 37. Here, substantially the same thiazole nucleus is attached via a bridging group to an N-methylthiourea. A similar disclosure is present for isothiazoles, oxazoles and isoxazoles. U.S. Pat. No. 4,022,797, a division, specifically claims the cyanoguanidine derivatives and U.S. Pat. No. 4,137,234, another division, specifically claims thioureas.
U.S. Pat. No. 4,000,296 discloses and claims a group of N-alkyl or N-arylsulfonyl-N'-alkyl-N"(heterocyclealkylthioalkyl)guanidines in which the heterocycle can be thiazole, isothiazole, oxazole or isoxazole. Alkyl, alkylaminoalkyl and alkyloxyalkyl bridging groups (connecting the heterocycle to the substituted guanidine group) are also disclosed. Substituted heterocycles belonging to any of the above classes are not disclosed. U.S. Pat. No. 4,166,856, originating with the Durant group, discloses and claims a number of imidazoles and thiazoles carrying the usual alkylthioalkyl-guanidine, -thiourea or -ethenediamine side chain, which side chain is invariably attached at the 2-position of the heterocyclic ring.
Another group of investigators under Yellin has disclosed--see U.S. Pat. Nos. 4,165,377, 4,234,735 and 4,165,378--certain novel thiazoles having a side chain such as those discussed above attached at the 4-position of the thiazole ring; i.e., an alkylthioalkyl-guanidine, -ethenediamine or -thiourea group attached thereto, but also bearing a guanidino group in the 2-position of the thiazole. Alkylene, alkenylene and alkyloxyalkyl bridging groups are also disclosed. A representative compound is 2-guanidino-4-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]thiazole which is said to have greatly increased activity over cimetidine.
A third research group at Allen and Hanburys Ltd. has prepared compounds with a furan ring carrying the standard alkylthioalkyl (or alkyloxyalkyl or alkyl) side chain terminating in a substituted guanidine or ethenediamine group, and also having a dialkylaminoalkyl substituent attached at a second position in the furan ring--see U.S. Pat. Nos. 4,128,658 and 4,168,855. Belgian Pat. Nos. 867,105 and 867,106 disclose the corresponding thiophene and aminoalkylbenzenes. Several of the compounds thus produced have a greater H.sub.2 -receptor antagonist activity than cimetidine. The most prominent of these new compounds is ranitidine: ##STR9##
U.S. Pat. No. 4,233,302 from Glaxo also discloses a group of H.sub.2 -receptor antagonists having a dialkylamino alkyl substituted thiophene or furan as one portion of the molecule.
Finally, a research group at Bristol-Myers have issued several United States patents involving different heterocycles. The first of these, U.S. Pat. No. 4,203,909, relates to furans carrying an alkylthioalkyl-guanidine (or thiourea or ethenediamine) side chain in the 2-position, an aminoalkyl side chain in the 5-position and an alkynylamino group as part of the terminal portion of the molecule. One of the compounds, 1-nitro-2-(2-propynylamino)-2-(2-[(5-dimethylaminomethyl-2-furyl)methylthi o]ethylamino)ethylene, is said to have 7.45 times the activity of cimetidine in a standard H.sub.2 -receptor assay. A second patent, U.S. Pat. No. 4,200,578, covers broadly thiazoles substituted with an alkylthioalkyl-guanidine (or thiourea or ethenediamine) side chain, and again carrying an obligatory alkynyl group in the terminal portion. Other permissible substituents in the thiazole ring include alkyl, guanidino or aminoalkyl.
Recently, Netherlands patent application 8004967, to Bristol-Myers published Sept. 1, 1980, same as U.K. Pat. No. 2,067,987, discloses a new and different and group, a 1,2,5-thiadiazole-1-oxide attached by a conventional bridging group to any of a number of hetero rings: ##STR10## wherein A can be phenyl, imidazolyl, furyl, thenyl, thiazolyl, etc substituted by a guanidino group or a dialkylaminoalkyl group. 2-[2-(dimethylaminomethyl)4-thiazolylmethylmercapto]ethylamine is specifically disclosed in Example 22. The same intermediate is disclosed by my copending application Ser. No. 193,192 filed Oct. 2, 1980 now U.S. Pat. No. 4,375,547.
More recently in the H.sub.2 -receptor antagonist art, there has been disclosed a new type of terminal group, a 4-pyrimidone group, ##STR11## to replace the cyanoguanidine or nitroethenediamine terminal group. This new group, when taken with the amino group terminating the bridging group, can be looked upon as a "ring-closed" guanidine with the imino group linked to the second amino group by a 3carbon fragment. For example, U.S. Pat. No. 4,255,428 discloses compounds of the formula: ##STR12## where Het can be a 2-thiazolyl radical (not substituted), Y is S or CH.sub.2 and Het.sup.1 is an hydroxypyridyl radical. Derwent Abstract 19764 D/12 discloses substituted pyrimidones attached by the conventional side chain to a N-containing heterocyclic ring which can be substituted with, among other groups, an amino group. Derwent Abstract 20656 D/12 discloses similar compounds in which the hetero ring can be a dialkylaminoalkyl substituted thiadiazole as do U.S. Pat. No. 4,234,585, and Belgian Pat. No. 877,889 wherein the heterocycle is a thiophene or furan permissibly substituted with a dialkylaminoalkyl group. A group of patents: U.S. Pat. Nos. 4,154,834 and 4,216,318 and South African Pat. Nos. 79/1617 and 79/1943 disclose compounds according to formula IV in which Het is an unsubstituted 2-thiazolyl group and Het.sup.1 can be, in one reference, a 3-pyridyl radical among a myriad of other aromatic groups. Finally, EPO Pat. No. 11728 discloses compounds according to formula IV in which Het is a 4-thiazolyl radical but in which there is a mandatory 2-guanidino group in the thiazole ring.